Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, People's Republic of China.
Department of General and Gastrointestinal Surgery, Suez Canal University, Ismailia, Egypt.
J Cell Biochem. 2019 Jun;120(6):10351-10362. doi: 10.1002/jcb.28319. Epub 2018 Dec 19.
Neoadjuvant chemoradiotherapy (CRT) resistance is a complex phenomenon and it remains a major problem for patients with a priori resistant tumor. Therefore, there is a strong need to investigate molecular biomarkers which may guide for treatment decision-making. In our study, weighted gene coexpression network analysis was applied to identify CRT-resistance hub modules in 12 colorectal cancer (CRC) cell lines with different CRT sensitivities from GSE20298 data set. The green module and purple module had the highest correlations with CRT resistance. Gene ontology enrichment analysis indicated that the function of these two modules focused on interferon-mediated signaling pathway, immune response, chromatin modulation, Rho GTPases activities, and regulation of apoptotic process. Then, 15 hub genes in both the coexpression and protein-protein interaction networks were selected. Among these hub genes, higher H2A histone family member J (H2AFJ) expression was independently validated in patient cohorts from two testing data sets of GSE46862 and GSE68204 to be related to CRT resistance. The receiver operating characteristic curve showed that H2AFJ could efficiently distinguish CRT-resistance cases from CRT-sensitive cases in another two testing data sets. Furthermore, meta-analysis of 12 Gene Expression Omnibus-sourced data sets showed that H2AFJ messenger RNA levels were significantly higher in CRC tissues than in normal colon tissues. High H2AFJ expression was correlated with a significant worse event- and relapse-free survival by analyzing the data from the R2: Genomics Analysis and Visualization Platform. Gene set enrichment analysis determined that the mechanism of H2AFJ-mediated CRT resistance might involve the ERK5 (MAPK7), human immunodeficiency virus Nef (HIV Nef), and inflammatory pathways. This study is the first, to the best of our knowledge, to implicate and verify H2AFJ as an effective new marker for CRT response prediction.
新辅助放化疗（CRT）耐药是一种复杂的现象，对于具有先天耐药肿瘤的患者来说仍然是一个主要问题。因此，强烈需要研究可能指导治疗决策的分子生物标志物。在我们的研究中，应用加权基因共表达网络分析从 GSE20298 数据集的 12 种对 CRT 敏感性不同的结直肠癌（CRC）细胞系中鉴定 CRT 耐药的核心模块。绿色模块和紫色模块与 CRT 耐药性的相关性最高。基因本体论富集分析表明，这两个模块的功能集中在干扰素介导的信号通路、免疫反应、染色质调节、Rho GTPases 活性和凋亡过程的调节。然后，从共表达和蛋白质-蛋白质相互作用网络中选择了 15 个核心基因。在这些核心基因中，更高的 H2A 组蛋白家族成员 J（H2AFJ）表达在来自 GSE46862 和 GSE68204 的两个测试数据集的患者队列中独立验证与 CRT 耐药性相关。受试者工作特征曲线表明，H2AFJ 可以有效地将 CRT 耐药病例与 CRT 敏感病例区分开来在另外两个测试数据集中。此外，对 12 个基因表达综合分析数据集的荟萃分析表明，CRC 组织中的 H2AFJ 信使 RNA 水平明显高于正常结肠组织。通过分析来自 R2：基因组分析和可视化平台的数据，高 H2AFJ 表达与事件和无复发生存率显著相关。基因集富集分析确定 H2AFJ 介导的 CRT 耐药的机制可能涉及 ERK5（MAPK7）、人类免疫缺陷病毒 Nef（HIV Nef）和炎症途径。这项研究是首次在最佳知识范围内暗示和验证 H2AFJ 作为 CRT 反应预测的有效新标志物。
